Method for treating schizophrenia and method and composition for potentiating neuroleptic drugs

ABSTRACT

A method for treating schizophrenia and a method and composition for potentiating the beneficial effects and reducing the side effects of neuroleptic drugs. Schizophrenia is treated with a GABA-like compound such as Lioresal. Neuroleptic drugs are potentiated by coadministering to a schizophrenic a neuroleptic drug and a GABA-like drug such as Lioresal.

RELATIONSHIP TO PRIOR APPLICATION

This application is a Continuation-in-Part of U.S. Ser. No. 475,856filed June 3, 1974, now U.S. Pat. No. 3,947,579.

BACKGROUND OF THE INVENTION BACKGROUND OF THE PRIOR ART

U.S. Pat. No. 3,471,548 describes compounds having the structuralformula ##STR1## wherein R is chloro, bromo, fluoro or fluoromethyl. Thecompounds are known to cross the blood brain barrier and are known tohave muscle relaxant properties and to be useful in the treatment in manof spasticity of spinal origin.

Neuroleptic drugs are used to treat schizophrenia. Examples of commonneuroleptic drugs include phenothiazines such as chloropromazine;butyrophenones such as haloperidol and others such as pimocide andclozapine. Side effects of neuroleptic drugs include sedation andtardive dyskinesias. The latter side effect is particularly importantbecause it results in involuntary muscle movements especially of theface and mouth which become irreversible. The onset of this side effectis directly related to the amounts of and length of time which aneuroleptic drug is used in treatment.

SUMMARY OF THE INVENTION

There has now been discovered a method for treating schizophrenia and amethod and composition for potentiating the beneficial effects and forreducing the side effects of neuroleptic drugs.

The foregoing results are obtained by administering to a schizophrenican effective amount of a gabergic compound or by coadministering to aschizophrenic a neuroleptic drug and a potentiating amount of a gabergiccompound such as γ-hydroxybutyrolactone, γ-hydroxybutyrate,aminooxyacetic acid, 5-ethyl-5-phenyl-2-pyrrolidone,1-hydroxy3-amino-2-pyrrolidone, or a compound having the structuralformula ##STR2## wherein R is halogen or trifluoromethyl and saltsthereof.

The present invention further relates to a composition comprising aneuroleptic drug and a potentiating amount of a gabergic compoundtogether with a suitable pharmaceutical carrier.

DETAILED DESCRIPTION OF THE INVENTION

Compounds having the foregoing structural formula such as, for example,β-(4-chlorophenyl)-γ-aminobutyric acid and pharmaceutically acceptablesalts thereof and pharmaceutical compositions thereof and their mannerof making is described in U.S. Pat. No. 3,471,548 and relevant portionsthereof are hereby incorporated by this reference.γ-hydroxybutyrolactone, γ-hydroxybutyrate and aminooxyacetic acid,5-ethyl-5-phenyl-2-pyrrolidone, 1-hydroxy-3-amino-2-pyrrolidone are alsoknown to those of skill in the art.

The amount of GABA-like or gabergic compound which may be used in thepresent invention ranges from about 0.1 to about 100 mg/kg andpreferably from about 0.1 to about 10 mg/kg and preferably about 0.1 to1.5 mg/kg per day.

The term "gabergic" compound herein refers to compounds which arerelated pharmacologically to γ-aminobutyric acid, known as GABA. Typicalexamples of GABA-like or gabergic compounds includeγ-hydroxybutyrolactone, γ-hydroxybutyrate, aminooxyacetic acid,5-ethyl-5-phenyl-2-pyrrolidone, 1-hydroxy-3-amino-2-pyrrolidone, andβ-(4-chlorophenyl)-γ-aminobutyric acid. When used herein, the term"gabergic compound" refers to any gabergic compound, such as, but notlimited to, the foregoing gabergic compounds.

Neuroleptic drugs which may be used in the present invention includephenothiazine derivatives such as chlorpromazine, promozine,triflupromozine, acetophenazine, butaperazine, corphenazine,fluphenazine, perphenazine, prochloroperazine, thiopropazate,trifluoperazine, mepazine, mesoridazine, piperacetazine, thioridazine,chloroprothizine, thiothixine, benzoctamine, cidorepin, clomacran,clopenthixol, clothiapine, clothixamide, clozapine, dimeprozan, doxepin,lovapine, perlapine and pinovepin; rauwolfia derivatives includingdeserpidine, metaserpate, rescinnamine, reserpine, bezquinamide,oxypertine, tetrabenazine, indopine, indriline, methopholine,milipertine, molindone, solypertine, yohimbine and solertine;diphenylmethane derivatives including benactyzine, piperilate,azacyclonal, captodiamine, hydroxyzine, cyprolidol, hexandrol andpimizide; and butyrophenone derivatives including haloanisone,haloperidol, oxaperone, benperidal, carperone, droperidal, fluspirilene,meperone, penfluridol, pipamperone, seperidol, spiperone andtrifluperidol. When used herein, the term "neuroleptic drugs" refers toany neuroleptic drug such as, but not limited to, the foregoingneuroleptic drugs.

While Applicant does not necessarily rely on the following theory ofaction as to why the gabergic compounds are useful in the treatment ofschizophrenia and to potentiate the effects of neuroleptic drugs,Applicant believes that known neuroleptic drugs act by blocking dopaminereceptor activity in the brain. However, whenever the dopamine receptoractivity is blocked, compensatory mechanisms are initiated by thecentral nervous systems to restore normal dopamine receptor activity.The compensatory mechanisms act by blocking the normal inhibitoryγ-aminobutyric acid (GABA) activity of dopamine cell bodies, thustending to increase dopamine neuron activity. Applicant believes thegabergic compounds selectively interfere with the compensatorymechanisms controlling activity in the mesolimbic dopamine neurons byincreasing GABA receptor activity in the medial dopamine cell bodies ofthe midbrain, which inervate the limbic forebrain and thereby potentiatethe effect of neuroleptic drugs by blocking the the increase of limbicdopamine turnover otherwise caused by the neuroleptic drug. In thismanner, the gabergic compound can be used to potentiate the beneficialeffects of neuroleptic drugs, since their antipsychotic effect isbelieved to be due to blockade of limbic dopamine receptors andthemselves have therapeutic benefit in the treatment of schizophrenia.Applicant further believes that extrapyramidal side effects, e.g.,tardive dyskinesia and parkinsonian-like side effects, are mediatedthrough the blockade of neostriatal dopamine receptors. Thus, whencoadministered with the foregoing neuroleptic drugs, the gabergiccompounds described herein allow the use of lower doses of neurolepticdrugs to obtain the same antipsychotic effect as obtained with higherdoses of neuroleptic drug without the gabergic compounds. At the sametime, neostriatal dopamine receptor blockade is reduced and thusextrapyramidal side effects are likewise reduced or eliminated. As aresult of the foregoing, the dose of neuroleptics now given may bedecreased by a factor of 2-20 times (about 5-50% of usual dose) whenco-administered with an effective amount of one of the gabergiccompounds of the present invention.

For purposes of this invention, the term "co-administered" means theadministration of a neuroleptic drug and a gabergic compound asdescribed herein to a patient during a course of treatment.

For purposes of this disclosure, the phrase "treatment of schizophrenia"means the temporary alleviation of at least some of the signs orsymptoms of schizophrenia.

The pharmaceutical compositions may be in a form suitable for oral use,for example, as tablets, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to provide apharmaceutically elegant and palatable preparation. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for manufacture of tables.These excipients may be, for example, inert diluents, for examplecalcium carbonate, sodium carbonate, lactose, calcium phosphate orsodium phosphate; granulating and disintegrating agents. for example,maize starch, or alginic acid; binding agents, for example starch,gelatine or acacia, and lubricating agents, for example magnesiumstearate or stearic acid. The tablets may be uncoated or they may becoated by known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules wherein the active ingredient is mixed with anoil medium, for example, arachis oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredients in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example, polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol, for example polyoxyethylene sorbitol monooleate, orcondensation product of ethylene oxide with partial ester derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The said aqueous suspensions may also contain one or morepreservatives, for example, ethyl, or n-propyl, p-hydroxy benzoate, oneor more coloring agents, one or more flavoring agents and one of moresweetening agents, such as sucrose, saccharin, or sodium or calciumcyclamate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients for example, sweetening, flavoring and coloringagents, may also be present

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, sorbitol or sucrose. Such formulations may alsocontain a demulcent, a preservative and flavoring and coloring agents.The pharmaceutical compositions may be in the form of a sterile,injectable preparation, for example as a sterile, injectable aqueoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butane diol.

The pharmaceutical compositions may b tableted or otherwise formulatedso that for every 100 parts by weight of the composition there arepresent between 5 and 95 parts by weight of the active ingredients andpreferably between 25 and 85 parts by weight of the active ingredients.The dosage unit form will generaly contain between about 10 mg and about500 mg of the active ingredients. A preferred dosage rate for oraladministration is of the order of 1-1000 mg daily, optionally in divideddoses.

From this foregoing formulation discussion, it it apparent that thecompositions of this invention can be administered orally orparenterally. The term "parenteral " as used herein includessubcutaneous injection, intravenous, intramuscular, or intrasternalinjection or infusion techniques.

This invention is further demonstrated by the following examples inwhich all parts are by weight.

EXAMPLE I

The effect of β-(4-chlorophenyl)-γ-aminobutyric acid Lioresal) on thepimozide-induced increase in dopamine fluorescence disappearance fromthe neostriatum and subcortical limbic areas of rats after treatmentwith α-methyltyrosine methyl ester.

Dopamine neuron nerve endings can be made to fluoresce strongly as aresult of the presence of stored dopamine. These stores of dopamine arenot static; there is a continual release, reuptake, degradation and denovo synthesis at the nerve ending.

α-methyltyrosine methyl ester is an inhibitor of dopamine synthesis.Fluorescence microscopy shows that α-methyltyrosine methyl esterdepletes dopamine stores. Therefore, α-methyltyrosine methyl ester maybe used to determine dopamine turnover in the nerve endings sinceturnover is directly proportional to the rate of dopamine depletion.

When dopamine receptors are blocked by drugs such as pimozide andhaloperidol, the dynamic state of dopamine at and in the nerve endingsincrease. This appears as an increased disappearance of fluorescenceafter administration of α-methyltyrosine methyl ester. This increaseresults from a compensatory response to the decreased stimulation of thenerve cells normally receiving the dopamine stimulation.

α-methyltyrosine methyl ester (H 44/68), an inhibitor of dopaminesynthesis, was given to male Sprague-Dawley rats i.p. in a dose of 250mg/kg 4 hrs before killing. β-(4-chlorophenyl)-γ-aminobutyric acid(Lioresal) was given i.p. in a dose of 10, 20 or 25 mg/kg 15 minutesbefore H 44/68. Pimozide was given i.p. in a dose of 1 mg/kg 2 hoursbefore H 44/68, and haloperidol in a dose of 5 mg/kg 1 hours before H44/68. The dopamine levels were determined by measuring histochemicalfluorescence. The fluorescence intensity reflects the amount of dopaminepresent. The fluorescence intensity was semi-quantitatively estimated oncoded slides. 3 = strong; 2 = moderate; 1 = weak; 1/2 = very weak.Number of animals is shown within parenthesis. Table 1 below tabulatesthe data obtained.

                                      Table 1                                     __________________________________________________________________________                         Fluorescence intensity                                   Treatment            Neostriatum                                                                             Limbic forebrain                               __________________________________________________________________________    No drug treatment  3 (4)     3 (4)                                            H44/68             0.5(1)                                                                            1(2) 1.5(2)                                                                         0.5(2)                                                                            1(2)                                                                              1.5(1)                                   Pimozide + H44/68  0(7)                                                                              0.5(1)                                                                              0 (7)                                                                             0.5(5).sup.d                                 Pimozide + Lioresal                                                                        0(2) 0.5(4)                                                                         1.5(2)                                                                            2(2)  1.5(4)                                                                            2(6).sup.e                                   (20) + H44/68                                                                 Pimozide + Lioresal                                                                        0(3) 0.5(3)                                                                         1  (2)                                                                            1.5(3)                                                                              1(1)                                                                              1.5(6)                                                                            2(4).sup.f                               (10) + H44/68                                                                 Haloperidol + H44/68                                                                             0.5(1)                                                                            1(6)  0.5(2)                                                                            1(6).sup.g                                   Haloperidol + Lioresal                                                                           1(4)                                                                              1.5(2) 2(1)                                                                         2(6)                                                                              2.5(2).sup.h                                 (10) + H44/68                                                                 Lioresal (25) + H44/68                                                                           1(1)                                                                              1.5(3)                                                                              1(1)                                                                              1.5(1)                                                                            2(2)                                     Lioresal (10) + H44/68                                                                           1.5(2)                                                                            2(1)  1.5(1)                                                                            2(1)                                                                              2.5(1)                                   __________________________________________________________________________

Statistical significance according to Tukey's Quick test:

    ______________________________________                                        d-e:    p < 0.001      g-h:   p < 0.001                                       d-f:    p < 0.001                                                             ______________________________________                                    

The foregoing Example I shows that the dopamine turnover at the nerveendings is increased by pimozide and haloperidol. This increase isantagonized by β-(4-chlorophenyl)-γ-aminobutyric acid in the limbicforbrain (nuc. accumbens, tuberculum olfactorium). Thus, as seen fromthe foregoing table, the increased disappearance (i.e. decrease inamount) of dopamine fluorescence from the limbic forebrain but not fromthe neostriatum seen after introduction of pimozide and haloperidol issignificantly counteracted by pre-treatment withβ-(4-chlorophenyl)-γ-aminobutyric acid.

It can thus also be stated that Lioresal can counteract the pimozideincrease in dopamine turnover also in the limbic cortex. This isimportant, since thought processes are usually linked to corticalregions and therefore these limbic dopamine receptors may beparticularly involved in the control of the abnormal thought processesfound in schizophrenia.

EXAMPLE II

Effect of γ-OH-butyrolactone on the pimozide-induced increase in DAfluorescence disappearance found after treatment with α-methyl tyrosinemethyl ester in rats (6-9).

The method used in Example I was followed. Pimozide was given i.p. in adose of 1 mg/kg 2 hrs before α-methyl tyrosine methyl ester (H44/68)(250 mg/kg, i.p., 2 hr). γ-OH-Butyrolactone was given i.p. 15 min.before H44/68 in a dose of 300 mg/kg. The results of the study showedthat γ-hydroxybutyrolactone selectively counteracted thepimozide-induced increases in dopamine turnover in the limbic system.

Thus, the foregoing Example II shows that γ-hydroxybutyrolactone alsopotentiates the antipsychotic action of neuroletpic drugs and at thesame time reduces extrapyramidal-like side effects of neuroleptic drugsby enabling a lowering of the dosage of the neuroleptic given. The studyalso showed that γ-hydroxybutyrolactone would also be useful alone inthe treatment of schizophrenia.

EXAMPLE III

Effect of Lioresal and aminooxyacetic acid (AOAA) on thepimozide-induced increase in dopamine fluorescence disappearance foundafter treatment with α-methyl tyrosine methyl ester in rats (9-10).

The method of Example I was followed, pimozide (1 mg/kg i.p. was given 2hrs before α-methyl tyrosine methyl ester (250 mg/kg, i.p. 2 hr beforefilling). Lioresal (5 mg/kg, i.p.) was given 15 min. before α-methyltyrosine methyl ester, as was aminooxyacetic acid (25 mg/kg, i.p.).

The results of the study showed that aminooxyacetic acid selectivelycounteracted the pimozide-induced increase in dopamine turnover in thelimbic system (nuc. accumbens, tuberculum olfactorium)

Thus, the foregoing Example III also shows that aminooxyacetic acidpotentiates the antipsychotic action of neuroleptic drugs and at thesame time lowers extrapyramidal side effects by enabling a lowering ofthe dosage of the neuroleptic given. The study also shows thataminooxyacetic acid would also be useful alone in the treatment ofschizophrenia.

EXAMPLE IV

Effect of 5-ethyl-5-phenyl- pyrrolidone (EPP) on the α-methyl tyrosinemethyl ester induced dopamine fuorescence disappearance in the nuc.caudatus, nuc. accumbens and tuberculum olfactorium of rats.

The method of Example I was followed. EPP was given i.p. in a dose of 50mg/kg 15 min. before α-methyl tyrosine methyl ester (H44/68) (250 mg/kg,i.p. 2 hr. before killing). The specific DA flourescense is given inarbitrary fluorescence units. A Leitz microspectrofluorometer was used.The number of animals used is shown within parenthesis. The data isreported as a mean ± s.e.m. in Table 2 below.

                                      Table 2                                     __________________________________________________________________________                   Dopamine fluorescence                                                    Tuberculum nuc.       nuc.                                          Treatment olfactorium                                                                          %   accumbens                                                                            %   caudatus                                                                             %                                      __________________________________________________________________________    No drug treatment                                                                       30.9 ± 1.8                                                                        100 52.3 ± 4.9                                                                        100 25.3 ± 1.3                                                                        100                                               (3)        (3)        (3)                                          H44/68    18.1 ± 1.5                                                                        58  29.8 ± 1.4                                                                        57  13.7 ± 0.8                                                                        54                                                (5)        (5)        (5)                                          EPP (50) +                                                                              28.7 ± 1.6                                                                        93  37.1 ± 1.2                                                                        71  14.4 ± 1.3                                                                        57                                     H44/68     (4)        (5)        (5)                                          __________________________________________________________________________

EXAMPLE V

The effect of Lioresal, aminooxyacetic acid (AOAA) and5-ethyl-5-phenyl-2-pyrrolidone (EPP) on the pimozide induced increase ofdopamine turnover in the dopamine terminal islands of the entorhinalcortex.

The method used in Example I was followed. Lioresal (10 mg/kg, i.p.),EPP (200 mg/kg, i.p.) and AOAA (25 mg/kg, i.p.) were administered 15min. and 2 hr. (AOAA) before the α-methyl tyrosine methyl ester (H44/68)injection (250 mg/kg, i.p. 1 hr before killing). Pimozide (1 mg/kg) wasgiven i.p. 2 hrs before the H44/68 injection.

The results of this study indicated that both EPP and AOAA, likeLioresal, counteracted the pimozide-induced increase in dopamineturnover in the entorhinal cortex. These results indicated that AOAA andEPP can selectively counteract the pimozide-induced increase in dopamineturnover in the limbic system including the important limbic corticalregion.

Thus, the foregoing study shows that gabergic drugs of the EPP type alsocan potentiate the antipsychotic action of neuroleptic drugs, and alsobe active as such in schizophrenia. At the same time, extrapyramidalside effects of neuroleptic drugs are reduced by gabergic drugs sincethey enable a lowering of dosage of the neuroleptic drug given.

EXAMPLE VI

Tablets, each containing 60 mg of the active combination can beprepared, for example, from the following ingredients:

    ______________________________________                                                                Mg.                                                   ______________________________________                                        β-(4-chlorophenyl)-γ-aminobutyric acid                                                       40                                                  Lactose                   95                                                  Wheat starch              54                                                  Gelatine                   6                                                  Arrowroot                 24                                                  Stearic acid               6                                                  Talcum                    15                                                  Chlorpromazine            10                                                                            250                                                 ______________________________________                                    

Preparation of the tablets -- The active ingredients are homogeneouslymixed with lactose and wheat starch and pressed through a 0.5 mm meshsieve. Gelatine is dissolved in 10 times its own weight of water; thepowder mixture is evenly moistened with this solution and kneaded untila plastic mass has formed which is then pressed through a 3 mm meshsieve, dried at 45°C and then sifted through a 1.5 mm mesh sieve.Arrowroot, stearic acid and talcum are finely sifted and worked into theresulting mixture, and the paste is then made up in the usual mannerinto tablets of 9 mm diameter and 250 mg weight.

EXAMPLE VII

Example VI is repeated, except a number of tablet formulations wereprepared using one of the following compounds in the place ofβ-(4-chlorophenyl)-γ-aminobutyric acid: γ-hydroxybutyrolactone,γ-hydroxybutyrate, aminooxyacetic acid, 5-ethyl-5-phenyl-2-pyrrolidoneand 1-hydroxy-3-amino-2-pyrrolidone; and one of the followingneuroleptic compounds in the place of chlorpromazine: fluphenazine,clozapine, resperpine and haloperidol.

I claim:
 1. A method for potentiating the neuroleptic activity ofphenothiazine derivatives having neuroleptic activity comprisingadministering to a schizophrenic about 5 to about 50 percent of aconventional dosage amount of a phenothiazine derivative havingneuroleptic activity and an amount equal to about 0.1 to about 100 mg/kgof aminooxyacetic acid or a pharmaceutically acceptable salt thereof. 2.A method for potentiating the neuroleptic activity of phenothiazinederivatives comprising administering to a schizophrenic about 5 to about50 percent of a conventional dosage amount of a phenothiazine derivativeselected from the group consisting of chlorpromazine and theoridazineand an amount equal to about 0.1 to about 10 mg/kg of aminooxyaceticacid or a pharmaceutically acceptable salt thereof.